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A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials.

ABSTRACT: Objective ?To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials. Study Design ?A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency, and association with GA in a mother-neonate linked cohort, comprising women with uncomplicated singleton pregnancies delivered at ?24 weeks' GA. Results ?Among 17,912 mother-neonate pairs, neonates were at a risk of numerous severe but infrequent morbidities. Clinically important, predominantly rare events were combined into a CE comprising neonatal mortality and morbidities, which decreased in frequency with increasing GA. The highest CE frequency occurred at <31 weeks. High frequency of respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis drove the CE. Median length of hospital stay was longer at all GAs in those with the CE compared with those without. Conclusions ?Descriptive epidemiological assessment and clinical input were used to develop a CE to measure neonatal benefit, comprising clinically meaningful outcomes. These empirical data and CE allowed trials investigating tocolytics to be sized appropriately.

SUBMITTER: Pimenta JM

PROVIDER: S-EPMC5842077 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials.

Pimenta Jeanne M JM Ebeling Myla M Montague Timothy H TH Beach Kathleen J KJ Abell Jill J O'Shea Michael T MT Powell Marcy M Hulsey Thomas C TC

AJP reports 20180101 1

<b>Objective</b> To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials. <b>Study Design</b> A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency ...[more]

PMID: 29527406

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Project description:Importance:Severe morbidity in very preterm infants is associated with profound clinical implications on development and life-course health. However, studies of racial/ethnic disparities in severe neonatal morbidities are scant and suggest that these disparities are modest or null, which may be an underestimation resulting from the analytic approach used. Objective:To estimate racial/ethnic differences in severe morbidities among very preterm infants. Design, Setting, and Participants:This population-based retrospective cohort study was conducted in New York City, New York, using linked birth certificate, mortality data, and hospital discharge data from January 1, 2010, through December 31, 2014. Infants born before 24 weeks' gestation, with congenital anomalies, and with missing data were excluded. Racial/ethnic disparities in very preterm birth morbidities were estimated through 2 approaches, conventional analysis and fetuses-at-risk analysis. The conventional analysis used log-binomial regression to estimate the relative risk of 4 severe neonatal morbidities for the racial/ethnic groups. For the fetuses-at-risk analysis, Cox proportional hazards regression with death as competing risk was used to estimate subhazard ratios associating race/ethnicity with each outcome. Estimates were adjusted for sociodemographic factors and maternal morbidities. Data were analyzed from September 5, 2017, to May 21, 2018. Main Outcomes and Measures:Four morbidity outcomes were defined using International Classification of Diseases, Ninth Revision, diagnosis and procedure codes: necrotizing enterocolitis, intraventricular hemorrhage, bronchopulmonary dysplasia, and retinopathy of prematurity. Results:In total, 582 297 infants were included in this study. Of these infants, 285 006 were female (48.9%) and 297 291 were male (51.0%). Using the conventional approach in the very preterm birth subcohort, black compared with white infants had an increased risk of only bronchopulmonary dysplasia (adjusted risk ratio [aRR], 1.34; 95% CI, 1.09-1.64) and a borderline increased risk of necrotizing enterocolitis (aRR, 1.39; 95% CI, 1.00-1.93). Hispanic infants had a borderline increased risk of necrotizing enterocolitis (aRR, 1.39; 95% CI, 0.98-1.96), and Asian infants had an increased risk of retinopathy of prematurity (aRR, 1.85; 95% CI, 1.15-2.97). In the fetuses-at-risk analysis, black infants had a 4.40 times higher rate of necrotizing enterocolitis (95% CI, 2.98-6.51), a 2.73 times higher rate of intraventricular hemorrhage (95% CI, 1.63-4.57), a 4.43 times higher rate of bronchopulmonary dysplasia (95% CI, 2.88-6.81), and a 2.98 times higher rate of retinopathy of prematurity (95% CI, 2.01-4.40). Hispanic infants had an approximately 2 times higher rate for all outcomes, and Asian infants had increased risk only for retinopathy of prematurity (adjusted hazard ratio, 2.43; 95% CI, 1.43-4.11). Conclusions and Relevance:In this study, racial/ethnic disparities in neonatal morbidities among very preterm infants appear to be sizable, but may have been underestimated in previous studies, and may have implications for the future. Understanding these racial/ethnic disparities is important, as they may contribute to inequalities in health and development later in the child's life.

Project description:BACKGROUND:Infants born very preterm are more likely to experience neonatal morbidities compared to their term peers. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities. METHODS:This study included 532 infants born?<?30 weeks gestation, participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants study. We used a neonatal morbidity risk score, which was an additive index of the number of morbidities experienced during the NICU stay, including bronchopulmonary dysplasia (BPD), severe brain injury, serious neonatal infections, and severe retinopathy of prematurity. DNA was collected from buccal cells at discharge from the NICU, and DNAm was measured using the Illumina MethylationEPIC. We tested for differential methylation in association with the neonatal morbidity risk score then tested for differentially methylated regions (DMRs) and overrepresentation of biological pathways. RESULTS:We identified ten differentially methylated CpGs (? Bonferroni-adjusted for 706,278 tests) that were associated with increasing neonatal morbidity risk scores at three intergenic regions and at HPS4, SRRD, FGFR1OP, TNS3, TMEM266, LRRC3B, ZNF780A, and TENM2. These mostly followed dose-response patterns, for 8 CpGs increasing DNAm associated with increased numbers of morbidities, while for 2 CpGs the risk score was associated with decreasing DNAm. BPD was the most substantial contributor to differential methylation. We also identified seven potential DMRs and over-representation of genes involved in Wnt signaling; however, these results were not significant after Bonferroni adjustment for multiple testing. CONCLUSIONS:Neonatal DNAm, within genes involved in fibroblast growth factor activities, cellular invasion and migration, and neuronal signaling and development, are sensitive to the neonatal health complications of prematurity. We hypothesize that these epigenetic features may be representative of an integrated marker of neonatal health and development and are promising candidates to integrate with clinical information for studying developmental impairments in childhood.

Project description:BACKGROUND:The correct dating of pregnancy is critical to support timely decisions and provide obstetric care during birth. The early obstetric ultrasound assessment before 14 weeks is considered the best reference to assist in determining gestational age (GA), with an accuracy of ±5 to 7 days. However, this information is limited in many settings worldwide. OBJECTIVE:The aim of this study is to analyze the association between the obstetric interventions during childbirth and the quality of GA determination, according to the first antenatal ultrasound assessment, which assisted the calculation. METHODS:This is a hospital-based cohort study using medical record data of 2113 births at a perinatal referral center. The database was separated into groups and subgroups of analyses based on the reference used by obstetricians to obtain GA at birth. Maternal and neonatal characteristics, mode of delivery, oxytocin augmentation, and forceps delivery were compared between groups of pregnancies with GA determination at different reference points: obstetric ultrasound assessment 14 weeks, 20 weeks, and ?20 weeks or without antenatal ultrasound (suboptimal dating). Ultrasound-based GA information was associated with outcomes between the interest groups using chi-square tests, odds ratios (OR) with 95% CI, or the Mann-Whitney statistical analysis. RESULTS:The chance of nonspontaneous delivery was higher in pregnancies with 14 weeks ultrasound-based GA (OR 1.64, 95% CI 1.35-1.98) and 20 weeks ultrasound-based GA (OR 1.58, 95% CI 1.31-1.90) when compared to the pregnancies with ?20 weeks ultrasound-based GA or without any antenatal ultrasound. The use of oxytocin for labor augmentation was higher for 14 weeks and 20 weeks ultrasound-based GA, OR 1.41 (95% CI 1.09-1.82) and OR 1.34 (95% CI 1.04-1.72), respectively, when compared to those suboptimally dated. Moreover, maternal blood transfusion after birth was more frequent in births with suboptimal ultrasound-based GA determination (20/657, 3.04%) than in the other groups (14 weeks ultrasound-based GA: 17/1163, 1.46%, P=.02; 20 weeks ultrasound-based GA: 25/1456, 1.71%, P=.048). Cesarean section rates between the suboptimal dating group (244/657, 37.13%) and the other groups (14 weeks: 475/1163, 40.84%, P=.12; 20 weeks: 584/1456, 40.10%, P=.20) were similar. In addition, forceps delivery rates between the suboptimal dating group (17/657, 2.6%) and the other groups (14 weeks: 42/1163, 3.61%, P=.24; 20 weeks: 46/1456, 3.16%, P=.47) were similar. Neonatal intensive care unit admission was more frequent in newborns with suboptimal dating (103/570, 18.07%) when compared with the other groups (14 weeks: 133/1004, 13.25%, P=.01; 20 weeks: 168/1263, 13.30%, P=.01), excluding stillbirths and major fetal malformations. CONCLUSIONS:The present analysis highlighted relevant points of health care to improve obstetric assistance, confirming the importance of early access to technologies for pregnancy dating as an essential component of quality antenatal care.

Project description:OBJECTIVE: To determine whether a short interval between pregnancies is an independent risk factor for adverse obstetric outcome. DESIGN: Retrospective cohort study. SETTING: Scotland. SUBJECTS: 89 143 women having second births in 1992-8 who conceived within five years of their first birth. MAIN OUTCOME MEASURES: Intrauterine growth restriction (birth weight less than the 5th centile for gestational age), extremely preterm birth (24-32 weeks), moderately preterm birth (33-36 weeks), and perinatal death. RESULTS: Women whose subsequent interpregnancy interval was less than six months were more likely than other women to have had a first birth complicated by intrauterine growth restriction (odds ratio 1.3, 95% confidence interval 1.1 to 1.5), extremely preterm birth (4.1, 3.2 to 5.3), moderately preterm birth (1.5, 1.3 to 1.7), or perinatal death (24.4, 18.9 to 31.5). They were also shorter, less likely to be married, and more likely to be aged less than 20 years at the time of the second birth, to smoke, and to live in an area of high socioeconomic deprivation. When the outcome of the second birth was analysed in relation to the preceding interpregnancy interval and the analysis confined to women whose first birth was a term live birth (n = 69 055), no significant association occurred (adjusted for age, marital status, height, socioeconomic deprivation, smoking, previous birth weight vigesimal, and previous caesarean delivery) between interpregnancy interval and intrauterine growth restriction or stillbirth. However, a short interpregnancy interval (< 6 months) was an independent risk factor for extremely preterm birth (adjusted odds ratio 2.2, 1.3 to 3.6), moderately preterm birth (1.6, 1.3 to 2.0), and neonatal death unrelated to congenital abnormality (3.6, 1.2 to 10.7). The adjusted attributable fractions for these associations were 6.1%, 3.9%, and 13.8%. The associations were very similar when the analysis was confined to married non-smokers aged 25 and above. CONCLUSIONS: A short interpregnancy interval is an independent risk factor for preterm delivery and neonatal death in the second birth.

Dataset Information

A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials.

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A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials.

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